Olfaction regulates organismal proteostasis and longevity via microRNA-dependent signaling.

The maintenance of proteostasis is crucial for any organism to survive and reproduce in an ever-changing environment, but its efficiency declines with age. Posttranscriptional regulators such as microRNAs control protein translation of target mRNAs with major consequences for development, physiology, and longevity. Here we show that food odor stimulates organismal proteostasis and promotes longevity in through -mediated inhibition of mRNA stability in olfactory AWC neurons. Screening a collection of microRNAs that control aging we find that miRNA regulates lifespan and promotes ubiquitin-dependent protein turnover, particularly in the intestine. We show that directly inhibits the toll receptor domain protein TIR-1 in AWC olfactory neurons and that disruption of or loss of AWC olfactory neurons eliminates the influence of food source on proteostasis. -mediated regulation of TIR-1 controls chemotactic behavior and is regulated by odor. Thus, odor perception influences cell-type specific miRNA-target interaction to regulate organismal proteostasis and longevity. We anticipate that the proposed mechanism of food perception will stimulate further research on neuroendocrine brain-to-gut communication and may open the possibility for therapeutic interventions to improve proteostasis and organismal health via the sense of smell, with potential implication for obesity, diabetes and aging.